There is now convincing evidence that an endogenous cannabinoid system exists in both the brain and periphery. The isolation and identification of endogenous cannabinoids, such as anandamide, 2-arachidonyl glycerol and noladin ether, have intensified efforts to understand the functional significance of endogenous cannabinoids. It was the discovery of the endocannabinoids that led to the formation of the current program project. Our major goal continues to be the establishment of the role of the endocannabinoid system in normal physiological processes as well as in disease states. This understanding is particularly relevant to the etiology of cannabis abuse as well as identification of therapeutic uses of cannabinoids. Cannabinoid research has produced tremendous advances in recent years; however, as is often the case, increased knowledge reveals the complexity of a biological system. We are now assured that endocannabinoids produce some of their effects through known cannabinoid receptors, yet they are also capable of acting at as-yet-unidentified sites. It is unclear whether endocannabinoids and the plant-derived tetrahydrocannabinoid (THC) activate endocannabinoids in an identical fashion. The synthesis, cellular uptake and metabolic degradation are all crucial for the actions of the endocannabinoids, but these processes are not yet fully understood. There are numerous suggestions that endocannabinoids are involved in neurodegenerative/neurological disorders, yet the mechanism responsible for these putative actions remain to be elucidated. The purpose of this proposal is to address the above questions using this multidisciplinary program that consists of five research projects and an administrative core. Each P.I. is an experienced researcher who will make a unique contribution. Professor Mechoulam proposes to isolate and identify other endogenous substances, conduct a synthetic program, and assess cannabinoids as neuroprotective and anti-inflammatory agents. Dr. Razdan will continue to provide novel and innovative probes to the other members of the program project. Research teams led by Drs. Martin and Pertwee will coordinate their pharmacological evaluations of endogenous ligands and their analogs in order to further the structure-activity relationships of agonists and antagonist at the CB1 receptor, establish the structure-activity relationships for non-CB1 cannabinoid receptors, investigate cannabinoid actions at vanilloid VR1 receptors and develop selective inhibitors for fatty acid amidohydrolase and the anandamide membrane transporter. Dr. Dewey will determine which signal transduction pathways are critical for endocannabinoid and exocannabinoid actions. This highly integrated research team will continue to work closely together toward the goal of defining the biological roles of endocannabinoids.